In most animals, normal immunoglobulin heavy chains are only well-expressed when coupled with their cognate light chains. In humans, lone heavy chains are found in heavy chain disease that is manifested by dysfunctional heavy chains that lack sequences of the variable heavy, the CH1, or the variable heavy and CH1 domains. Heavy chains devoid of light chains are encountered in certain species of fish and in camels. Such heavy chains lack a functional CH1 domain and have non-human features in their heavy chain variable domains. Attempts have been made to make camelized antibodies by modifying mice to express camelized genes that mimic VHH domains found in camels or certain species of fish, in part by removal of IgM and IgG CH1 domains and conforming the heavy chain variable regions to resemble those of camels and/or certain species of fish. However, camelized antibodies would be expected to induce immune responses in non-camel animals.
There is a need in the art for genetically modified non-human animals that make heavy chain antibodies that have non-camelid VH domains.